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. 2018 Aug;27(8):899-907.
doi: 10.1158/1055-9965.EPI-17-1174. Epub 2018 May 22.

Genomic-Epidemiologic Evidence That Estrogens Promote Breast Cancer Development

Fritz F Parl  1 , Philip S Crooke  2 , W Dale Plummer Jr  3 , William D Dupont  3
Affiliations

Genomic-Epidemiologic Evidence That Estrogens Promote Breast Cancer Development

Fritz F Parl et al. Cancer Epidemiol Biomarkers Prev. 2018 Aug.

Abstract

Background: Estrogens are a prime risk factor for breast cancer, yet their causal relation to tumor formation remains uncertain. A recent study of 560 breast cancers identified 82 genes with 916 point mutations as drivers in the genesis of this malignancy. Because estrogens play a major role in breast cancer development and are also known to regulate the expression of numerous genes, we hypothesize that the 82 driver genes are likely to be influenced by estrogens, such as 17ß-estradiol (E2), and the estrogen receptor ESR1 (ERα). Because different types of tumors are characterized by unique sets of cancer driver genes, we also argue that the fraction of driver genes regulated by E2-ESR1 is lower in malignancies not associated with estrogens, e.g., acute myeloid leukemia (AML).Methods: We performed a literature search of each driver gene to determine its E2-ESR1 regulation.Results: Fifty-three of the 82 driver genes (64.6%) identified in breast cancers showed evidence of E2-ESR1 regulation. In contrast, only 19 of 54 mutated driver genes (35.2%) identified in AML were linked to E2-ESR1. Among the 916 driver mutations found in breast cancers, 813 (88.8%) were linked to E2-ESR1 compared with 2,046 of 3,833 in AML (53.4%).Conclusions: Risk assessment revealed that mutations in estrogen-regulated genes are much more likely to be associated with elevated breast cancer risk, while mutations in unregulated genes are more likely to be associated with AML.Impact: These results increase the plausibility that estrogens promote breast cancer development. Cancer Epidemiol Biomarkers Prev; 27(8); 899-907. ©2018 AACR.

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Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1
Manhattan plot of p-values for the association between breast cancer or AML and point mutations in driver genes for these two cancers. In this cross-sectional study, all subjects had either breast cancer of AML. The p-values in the upper panel indicate an increased risk of breast cancer given that the patient has one or the other of these cancers. P-values in the lower panel are similarly defined but indicate an increased risk of AML. Each p-value is color-coded by whether or not the associated gene is E2-ESR1 regulated, and the marker shapes indicate whether the associated driver gene is for breast cancer only, AML only, or for both cancers. The Bonferroni-corrected significance level of 4.5×10−4 is indicated by blue, dashed lines.
Figure 2
Figure 2
Bar graphs showing mutational spectra of driver gene substitutions in (A) E2-ESR1-regulated and unregulated breast cancer driver genes and (B) shared driver genes of breast cancer and AML patients.
See this image and copyright information in PMC

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